Mucosal delivery is less often employed with rescue therapeutics because of challenges in effecting rapid mucosal delivery of therapeutically effective blood levels. The challenge of mucosal delivery of therapeutics has very plain real world implications for patients.
For example, the current mainline treatment for the treatment of breakthrough seizure control—particularly in pediatric patients—is Diastat®. Diastat® is a rectally administered diazepam gel. That a parent or guardian must take the time to disrobe a child in active seizure to rectally administer a rescue therapeutic speaks to both the reality of the challenge of oromucosal delivery (i.e. that there is not an oral alternative), and to the unmet medical need that is addressed by certain embodiments of the present invention. See, https://www.accessdata.fda.gov/drugsatfda_docs/ . . . /020648s008lbl.pdf and https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/013263 s083lbl.pdf, the contents of which are incorporated herein by reference.
Migraine and post-operative pain are frequently treated with narcotic analgesics—because safer pharmaceutical agents like non-steroidal anti-inflammatory drugs cannot be absorbed rapidly enough and at sufficient blood levels to effectively treat the symptoms—despite the fact that narcotic analgesics carry a known risk of subsequent abuse and addiction.
Yet another example of an unmet rescue therapeutic need is the use of naloxone hydrochloride to treat opioid overdose. See, generally, https://pubchem.ncbi.nlm.nih.gov/compound/5284596, the content of which is incorporated herein by reference. The only current treatment options are injectable drugs (which present needle stick risk), and intranasal delivery (which may be contraindicated for certain patient populations).
Other unmet rescue therapeutic needs are rapid delivery of anxiolytics for panic attack and other anxiety disorders; anti-emetics for post-operative nausea and motion sickness; bronchodilators for anaphylactic shock; anti-hypertensives for emergency treatment of high blood pressure; and anti-allergenics for treatment of hypersensitivity and allergic reactions.
Naloxone hydrochloride is a specific and effective opioid antagonist which acts competitively at opioid receptors in the brain and has been found to have a wide variety of medical uses, for example, in reversing of the effects of therapeutic or overdose quantities of opioid narcotic drugs. Thus, intravenous, intramuscular or subcutaneous naloxone hydrochloride is used in diagnosis and treatment of opioid overdose and is also administered post-operatively to reverse central nervous system depression resulting from the use of opioids during surgery.
Naloxone is also used for treatment of overdose of illicit opioid narcotics. The most common method of treatment is the use of an injectable naloxone product (or the newer product EVZIO™) which are available in the United States. These injectable products are commonly used in emergency room settings, and are also sometimes carried by law enforcement officials to rapidly reverse opioid overdose. A nasally administered naloxone spray to deliver an emergency dose of naloxone is also available in some countries. In the USA, the injectable product is currently used along with Mucosal Atomization Device (MAD™). The USA has also approved NARCAN™ nasal spray. Injectable and nasal naloxone are effective but not adequately portable to be routinely and conveniently carried on one's person. Furthermore, training is required for the administration of these products which may limit their widespread availability and use. See, www.accessdata.fda.gov/drugsatfda_docs/label/2015/208411lbl.pdf, the content of which is incorporated herein by reference.
Moreover, there are certain questions of the reliability of intranasal delivery for certain patient populations, as more fully described in the Citizen Petition of Mucodel Pharma available here: https://www.regulations.gov/document?D=FDA-2017-P-0428-0001.
Some narcotic antagonists can also be used to dissuade addictive behavior. U.S. Pat. Nos. 8,673,355 and 7,749,542 and 7,419,686 and 7,172,767 and 6,696,066 and 6,475,494 and 6,277,384 teach the combination of an opioid antagonist and an opioid agonist to discourage patients from diverting the product for illicit parenteral use. However, these patents provide no teaching as to the delivery of an opioid antagonist by itself. Other patents related to the field of the present invention include U.S. Pat. Nos. 8,652,515, 8,524,275, 8,017,148, 7,842,307, 7,718,192, 7,682,634, 7,332,182, 7,144,587, 6,627,635, and 8,475,832. These patents and their contents are incorporated into this specification by reference and as if they were fully set forth herein.
U.S. Pat. No. 8,475,832 teaches the combination of an agonist and antagonist and discusses the use of buffers to limit the absorption of Naloxone in the oral cavity using a buffer with a pH of 3-4. However, there is neither a mention of optimizing the absorption of an antagonist, nor mention of how to stabilize the antagonist during storage. U.S. Pat. No. 7,682,634 teaches the use of seal coatings to keep the agonist and the antagonist separated. But again, this art is directed to a combination of the agonist (opioid) and the antagonist (naloxone). These patents and their contents are incorporated by reference in this specification and as if they were fully set forth herein.
Ionizable pharmaceutically active compounds may be classified by their charge state properties as either basic, acidic or zwitterionic. Generally speaking, acidic drugs tend to be more soluble at basic pH and basic drugs would be more soluble at acidic pH. In solution, basic drugs would have a larger fraction existing as the ionized/unprotonated species at a pH below their pKa. On the other hand, they would be predominantly unionized/protonated at a higher pH above their pKa. In solution, acidic drugs would have a larger fraction in the ionized state at higher pH while at lower pH the drug would be predominantly unionized. Bases include, inter alia, aliphatic amines, anilines, basic amides, amidines, guanidines and heterocyclic nitrogen atoms. Drugs with acidic groups include, inter alia, carboxylates, phenols, sulfonamides and also heterocyclic nitrogen atoms and less commonly phosphates, tetrazoles, thiols, alcohols carbamates, hydrazides, imides and sulfates.
The term pharmaceutically active agent herein includes free acids and free bases as well as their salt forms. Pharmaceutical salt refers to an ionizable drug that has been combined with a counter-ion to form a neutral complex. Converting a drug into a salt through this process can increase its chemical stability, render the complex easier to administer and allow manipulation of the pharmaceutically active agent's equilibrium solubility and pharmacokinetic profile. The term pharmaceutically active agent may also mean racemic mixtures of the left- and right-handed enantiomers of chiral drugs or a single purified enantiomer with biological activity.
It is generally accepted that the permeation of ionizable molecules follows the pH-partition theory as explained by Chen et al, A mechanistic analysis to characterize oromucosal permeation properties. Int. J. of Pharmaceutics 184 (1999) 63-72, using nicotine as a model substance. The pH-partition theory was proved from the observations that permeability, partition coefficient and diffusivity of nicotine, varied as a function of pH. The neutral unionized nicotine species had a higher permeability than the ionized species due to its higher partition coefficient and diffusivity via the transcellular pathway. It is generally understood that neutral molecules are more readily able to traverse non-polar lipidic membrane environments, whereas this process is energetically disfavored for charged compounds. Acid/base character and pKa values are thus generally considered important determinants for absorption and permeation, however it is recognized that other factors such as lipophilicity, molecular size, metabolic lability, hydrophilicity and efflux mechanisms can also influence absorption.
Vishwas, Rai, Hock S. Tan, Bozena Michniak-Kohn, “Effects of Surfactants and pH on Naltrexone (NTX) Permeation Across Buccal Mucosa” Int. J. Pharm. Jun. 15, 2011; 411(1-2): pp 92-97 (“Vishwas et al.”) teaches the benefits of maintaining a pH of 6.8 to 8.2 for improved absorption of Naltrexone. For example, Vishwas et al states: “[s]lightly increasing the pH of NTX (naltrexone) from 6.8 to pH 7.5 and pH 8.5 increased permeation by a factor of 1.6 and 4.4 respectively.” Id. at page 8, Conclusions, Section 4, Sentence 5. Naltrexone is an antagonist with a structure much like Naloxone but has a better affinity for the κ-opioid binding site. Vishwas et al. further teach the use of a particular surfactant to increase the buccal absorption of Naltrexone: “It was found that permeation of NTX across reconstituted human buccal mucosa produced an enhancement of 7.7 with the use of Brij 58.” Id. at page 8, Conclusions, Section 4, Sentence 2. However, Vishwas et al. make no mention or suggestion of combining a surfactant with a pH buffer nor do they mention the use of two compartments to separate the buffer from the antagonist during the storage of the product. Nor do they teach how to have a storage-stable antagonist with a pH greater than 5 at the point of use.
Naloxone hydrochloride injection is formulated at a pH of approximately 4 to ensure chemical stability and physical stability below the equilibrium solubility of naloxone hydrochloride over the life of the product. The pKa of Naloxone is reported to be around 7.9 for the protonated amine. Based upon pH partition theory it may be expected that if the protonated unionized species has higher permeability through the oral mucosa, then maximal absorption could be expected at or around pH 7.9. However, sufficient absorption to elicit a therapeutic response could conceivably occur at pH greater than 5 and up to 12.
U.S. Pat. No. 6,110,926 teaches that aqueous solutions of Naloxone with buffers at pH 6.5 are subject to degradation and tests have shown that such solutions are in fact unstable, the naloxone content degrading over the course of a few days. This patent claims that the instability may explain the report by Loimar et al (The Lancet, May 5, 1990, pp. 1107-1108) that conjunctival naloxone does not provide a decision aid in determining opioid addiction. This patent and the Lancet paper, and their contents, are incorporated by reference into this specification as if fully set forth herein. It must also be noted that injectable naloxone is typically at a pH of 4 adjusted with hydrochloric acid presumably to avoid this instability.
Again, using naltrexone as an example, according to Vishwas et al., a pH of 6.5 is in the target pH range for optimizing the bioavailability (absorption) of the antagonist. However, neither the patents referenced above, nor Vishwas et al., teach how to both optimize the absorption of the antagonist and also protect the antagonist from pH-induced oxidation or hydrolysis during storage.
A rescue drug like naloxone cannot be administered orally to an unconscious patient who is unable to swallow an oral medication. Similar issues are seen with other rescue therapeutics. For example, a child in seizure cannot be instructed to swallow an oral medication. It may be difficult for a patient with severe migraine or post-operative pain to swallow a conventional oral dosage form. Similarly, patients with conditions like Parkinson's frequently have difficulty swallowing. Moreover, even if the patient can swallow an oral medication, it may simply take too long to reach efficacious blood levels.
However, even if Naloxone or like antagonists were given orally using conventional methods, they would be subject to first pass metabolism, and degradation and are consequently not bioavailable for blocking of the opioid receptors at the relevant receptor sites in the body. Smith K; Hopp M; Mundin G; Bond S; Bailey P; Woodward J; Bell D. Low Absolute Bioavailability of Oral Naloxone in Healthy Subjects, “Int. J. of Clinical Pharmacology and Therapeutics, 2012; 50 (5); pp 360-367” (“Smith et al.”) and Manir A. Hussain; Bruce J. Aungst; Albert Kearney; Eli Shefter “Int. J. of Pharmaceutics, Vol. 36, Issues 2-3, May 1987, pp 127-130” (“Hussain et al.”) teach low systemic bioavailability of naloxone and naltrexone due primarily to metabolization by the liver. Smith writes “The mean absolute bioavailability of naloxone from the orally administered PR tablets was very low, ranging from 0.9% for the 5 mg dose to 2% for 40, 80, and 120 mg doses based on AUCt.” See Abstract Results, Sentence 1. Hussain writes “Both naloxone and naltrexone have been shown to be absorbed from the gastrointestinal tract. However, as a consequence of rapid clearance by the gut and/or liver, naloxone and naltrexone undergo extensive first-pass metabolism when given orally.” See id., page 129, 2. The major metabolite is naloxone-3-glucuronide which is excreted in the urine. The foregoing references and their contents (including the references in preceding paragraphs) are incorporated into this patent application by reference and as if fully set forth herein.
Although the prior art has taught the use of buffers and permeation enhancers to increase the buccal absorption of an antagonist, no one has taught how to deliver a shelf life stable buffered solution of an opioid antagonist at the point of absorption and for this reason applicant believes that there is no buccal opioid antagonist product in the market for life saving and other medical purposes.
A major problem with Naloxone is that it is only stable and soluble in a low pH environment e.g., a pH of 5 or less and preferably at pH 4 or lower, but that it needs to be at a higher pH (e.g. a pH greater than 5 and up to a pH of 12) in order for maximum mucosal absorption of the drug. Therefore, there exists a need for a convenient method to administer an opioid antagonist like Naloxone that is stable over the shelf-life of the product but that can successfully deliver naloxone at high pH at the site of absorption. This invention teaches a way to administer a chemically stable (during storage) aqueous liquid or semisolid gel dosage form of an antagonist through a mucosal administration site, such as the oromucosal region (which encompasses buccal, sublingual and gingival areas), intranasal, vaginal or rectal. The invention shows how to achieve the contrasting requirements for stability and solubility at storage pH and adequate active absorption pH for pharmaceutical active agents in a single dosage unit encompassing two chambers.